Intermediates and methods for the synthesis of halichondrin B analogs

ABSTRACT

Methods of synthesizing intermediates useful for the synthesis of halichondrin B analogs are described.

BACKGROUND OF THE INVENTION

The invention relates to a method for the synthesis of halichondrin Band analogs thereof having pharmaceutical activity, such as anticanceror antimitotic (mitosis-blocking) activity. B-1939 (also known as E7389or eribulin), a halichondrin B analog, has been reported to be usefulfor treating cancer and other proliferative disorders includingmelanoma, fibrosarcoma, leukemia, colon carcinoma, ovarian carcinoma,breast carcinoma, osteosarcoma, prostate carcinoma, lung carcinoma, andras-transformed fibroblasts.

Halichondrin B is a structurally complex marine natural productcontaining multiple chiral centers on an extended carbon framework. Dueto the limited availability of halichondrin B from natural sources,methods for the synthesis of halichondrin B have value for the purposesof developing the full medicinal potential of halichondrin B analogs. Amethod for the synthesis of halichondrin B analogs was published in 1992(Aicher, T. D. et al., J. Am. Chem. Soc. 114:3162-3164). A method forthe synthesis of Halichondrin B analogs, including B-1939, was describedin WO 2005/118565 (EISAI COMPANY, LTD.). The method described in WO2005/118565 has several practical advantages over the method disclosedby Aicher, including but not limited to the discovery of severalcrystalline intermediates which enabled increased quality control,reproducibility, and throughput. Not withstanding these advantages,several throughput limiting chromatographic purifications remainedparticularly relating to the C14-C26 fragment. For example, the C14-C26fragment contains 4 chiral centers at C17, C20, C23, and C25 whichrequire chromatography to control the quality of this fragment. Morespecifically, installment of the C25 chiral center does not occur withhigh selectivity and could not be practically enhanced due to a lack ofcrystalline intermediates late in the C14-C26 synthesis.

What is needed is a more efficient, less costly, more practical methodfor the synthesis of halichondrin B analogs, in particular B-1939.

SUMMARY

The current invention relates to a method for the synthesis ofHalichondrin B analogs, such as B-1939, from (−)-quinic acid accordingto the process illustrated in Scheme 1, below. The method introduces anumber of new and crystalline intermediates which greatly improve thestereochemical quality of the compounds synthesized and reduces the needfor chromatographic steps. Unlike the previously described methods, thepresently claimed method is substantially more appropriate forpharmaceutical manufacturing.

The invention also pertains to the novel intermediates disclosed herein.

WO 2005/118565 disclosed a method for making Halichondrin B analogs,such as B-1939, that included synthetic routes for (1) producing thecompound of formula Ia from (−)-quinic acid, and for (2) producing theB-1939 from Compound AG. Both synthetic routes are suitable for use inthe method of the present invention, and are incorporated by referenceherein.

The method of the present invention differs from the method disclosed inWO 2005/118565 in the process of synthesizing Compound AH from CompoundAA. In particular, the present invention discloses highly efficientmethods for generating the C25 chiral center, marked with an asterisk(*) in the relevant compounds in Scheme 1, by a process of equilibratingand selectively crystallizing the desired C25 isomer via analpha-methylated nitrile. In the method described in WO 2005/118565,Compound AH is synthesized by adding a methyl group to Compound AG, asshown above. This reaction generates the C25 chiral center. The productof that reaction is a mixture of diastereomers with each possibleconfiguration around that chiral center. Chromatography can be used topartially isolate Compound AH from the mixture of diastereomers, asdisclosed in WO2005/118565; however, the remaining diastereomers ofCompound AH result in undesired impurities in subsequent reaction steps,impurities which can only be removed through additional purificationprocedures.

Unlike the methods of syntheses of halichondrin B analogs previouslydescribed, the method of the present invention involves the formation ofthe C25 chiral center at an earlier stage in the synthesis of CompoundAH. Several of the methylated intermediates, including Compound AD andCompound AF are crystallizable. By crystallizing one or more of themethylated intermediates in accordance with the methods of the presentinvention, one can produce a composition of comprising Compound AH thatis substantially diastereomerically pure. For example, Compound AC canbe methylated to produce Compound AD. When Compound AD is produced, athe C25 chiral center is produced, the same chiral center discussed withrespect to Compound AH. When this reaction occurs, a diastereomericmixture is produced with each possible stereomeric configuration aroundthat chiral center. Although the methylation itself occurs with lowstereoselectivity, surprisingly, the desired diastereomer of Compound ADstereoselectively crystallizes. Moreover, the undesired C25 stereoisomercan be epimerized under conditions from which the desired C25stereoisomer crystallizes. Thus, the yield and quality of the C25stereoisomer can be enhanced by crystallization induced dynamicresolution (CIDR).

Several other intermediates produced in the synthetic route fromCompound AD to Compound AH can also be crystallized from reactionmixtures, resulting in an even higher purity composition of Compound AHthan could be produced by previously disclosed methods. In particular,Compound AF is a crystalline compound, while the correspondingnon-methylated Compound AE requires chromatography for purification.Compound AF may be synthesized from Compound AD or it can be synthesizedby methylating Compound AE.

Removal of chromatography steps from the processes used to synthesizehalichondrin B analogs dramatically increases the product yield andreproducibility, while decreasing cost and production time. The presentmethod also enables one to resolve difficult to resolve chiral centersat a considerably earlier points in the process, even as early as theproduction of Compound AH and Compound AI. B-1939 is suitablysynthesized from Compound AI using methods such as those described inWO/2005/118565.

In one embodiment, the invention pertains, at least in part, to a methodof obtaining a substantially diastereomerically pure compositioncomprising a compound of formula (I). The method includes crystallizingthe compound of formula (I) from a mixture of diastereomers underappropriate crystallization conditions, such that a substantiallydiastereomerically pure composition comprising a compound of formula (I)is formed. The compound of formula (I) is:

wherein:

z is a single or double bond, provided that when z is a double bond, X²is C and Y¹ is hydrogen; and provided that when z is single bond, X² isCH or O;

X¹ is O, S, or CN, provided that when X¹ is CN or S, X² is O;

Y¹ is a halide, hydrogen or O-L², or absent when X² is O; and

L¹ and L² are independently selected from hydrogen and a protectinggroup, or L¹ and L² together are a protecting group, provided that whenX¹ is CN, L¹ is absent; and salts thereof. The invention also pertainsto compositions of compounds of formula (I) that are substantially freeof diastereomers, as well as compounds of formula (I).

In another embodiment, the invention also pertains to a method of makinga diastereomerically pure composition of a compound of formula (Ib) froma compound of formula (Ia), wherein the compound of formula (Ia) is:

and the compound of formula (Ib) is:

wherein L^(1a) and L^(1b) are independently selected from hydrogen and aprotecting group, or L^(1a) and L^(1b) together are a divalentprotecting group, provided that L^(1a) of formulae (Ia) and (Ib) are thesame and L^(1b) of formulae (Ia) and (Ib) are the same. When L^(1a) orL^(1b) is a protecting group, it is preferably selected from the groupconsisting of C₁-C₆ alkyl ethers, aryl (C₁-C₆) alkyl ethers, silyl(C₁-C₁₀) ethers, C₁-C₆ alkyl esters, cyclic C₁-C₆ acetals, cyclic C₂-C₇ketals, and cyclic carbonates. The method includes reacting the compoundof formula (Ia) under alkylating conditions to form a mixture comprisingthe compound of formula (Ib) and diastereomers thereof; andcrystallizing the compound of formula (Ib) from the mixture, underappropriate crystallization conditions.

In another embodiment, the invention pertains, at least in part, to amethod of obtaining a substantially diastereomerically pure compositioncomprising a compound of formula (II). The method includes crystallizingthe compound of formula (II) from a mixture of diastereomers undersecond appropriate crystallization conditions, such that a substantiallydiastereomerically pure composition comprising a compound of formula(II) is formed. The compound of formula (II) is:

wherein:

c is a single or double bond, provided that when c is a double bond m isO and Y³ is O or CHCO₂-L³, and provided that when c is a single bond mis 0 or 1 and Y³ is CH₂O-L³, CH₂CO₂-L³ or CH₂CH₂O-L³;

Y² is C₁-C₇ sulfonate, O-L⁴ or a halide;

L⁴ is hydrogen or a protecting group; and

L³ and L⁵ are each independently hydrogen or a protecting group, or L³and L⁵ together are a protecting group, or a salt thereof. The inventionalso pertains to compositions of compounds of formula (II) that aresubstantially free of diastereomers, as well as compounds of formula(II).

In yet another embodiment, the invention also pertains to compounds offormula (III):

wherein: L⁶ is hydrogen or a protecting group; and salts thereof.

In yet another embodiment, the invention also pertains to a compositioncomprising a compound of formula (IIIa):

L^(6a), L^(6b), L^(6c) are each protecting groups, or a salt thereof,and wherein the composition is substantially free of diastereomers.

Furthermore, the invention also pertains to a composition comprising acompound selected from the group consisting of formula (I), (Ia), (Ib),(Ic), (Id), (Ie), (II), (IIa), (IIb), (III) and (IIIa). The inventionalso pertains to each of the compounds described in herein.

DETAILED DESCRIPTION

The current invention pertains, at least in part, to methods andintermediates for the preparation and crystallization of intermediatesand other compounds useful in the synthesis of halichondrin B and itsanalogs.

A. Definitions

In order that the present invention may be more readily understood,certain terms are first defined. Additional definitions are set forththroughout the detailed description.

The term “acetyl” refers to both acyl groups (e.g., —C(═O)—CH₃) andC₁-C₈ alkyl substituted carbonyls (e.g., —C—(═O)—(C₁-C₇)alkyl)).Preferably, the acetyl group is acyl.

The term “alkyl” refers to saturated hydrocarbons having one or morecarbon atoms, including straight-chain alkyl groups (e.g., methyl,ethyl, propyl, butyl, pentyl, hexyl, etc.), cyclic alkyl groups (or“cycloalkyl” or “alicyclic” or “carbocyclic” groups) (e.g., cyclopropyl,cyclopentyl, cyclohexyl, etc.), branched-chain alkyl groups (isopropyl,tert-butyl, sec-butyl, isobutyl, etc.), and alkyl-substituted alkylgroups (e.g., alkyl-substituted cycloalkyl groups andcycloalkyl-substituted alkyl groups). The terms “alkenyl” and “alkynyl”refer to unsaturated aliphatic groups analogous to alkyls, but whichcontain at least one double or triple carbon-carbon bond respectively.

The term “alkoxy” refers to alkyl groups linked to the remainder of themolecule through an oxygen atom. Examples of alkoxy groups include, butare not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, andpentoxy groups. The alkoxy groups can be straight-chain or branched.Preferable alkoxy groups include methoxy.

The term “heterocyclic group” refers to closed ring structures analogousto carbocyclic groups in which one or more of the carbon atoms in thering is an element other than carbon, for example, nitrogen, sulfur, oroxygen. Heterocyclic groups may be saturated or unsaturated.Additionally, heterocyclic groups (such as pyrrolyl, pyridyl,isoquinolyl, quinolyl, purinyl, and furyl) may have aromatic character,in which case they may be referred to as “heteroaryl” or“heteroaromatic” groups. Exemplary heterocyclic groups include, but arenot limited to pyrrole, furan, thiophene, thiazole, isothiaozole,imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine,pyrazine, pyridazine, pyrimidine, benzoxazole, benzodioxazole,benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl,quinoline, isoquinoline, napthridine, indole, benzofuran, purine,benzofuran, deazapurine, or indolizine.

The term “amine” or “amino,” refers to unsubstituted or substitutedmoiety of the formula —NR^(a)R^(b), in which R^(a) and R^(b) are eachindependently hydrogen, alkyl, aryl, or heterocyclyl, or R^(a) andR^(b), taken together with the nitrogen atom to which they are attached,form a cyclic moiety having from 3 to 8 atoms in the ring. Thus, theterm amino includes cyclic amino moieties such as piperidinyl orpyrrolidinyl groups, unless otherwise stated.

Regarding connectivity, an “arylalkyl” group, for example, is an alkylgroup substituted with an aryl group (e.g., phenylmethyl (i.e.,benzyl)). An “alkylaryl” moiety is an aryl group substituted with analkyl group (e.g., p-methylphenyl (i.e., p-tolyl)). Thus, the termimidazolyl-alkyl refers to an alkyl group substituted with an imidazolylmoiety.

The term “sulfonate” refers to moieties of the formula: R—SO₂—O—,wherein R is C₁-C₄ alkyl or C₆-C₈ aryl. Examples of sulfonates include,methanesulfonate (mesylate), trifluoromethanesulfonate (triflate),p-toluenesulfonate (tosylate), and benzenesulfonate (bensylate).

As used in the description and drawings, an optional single/double bondis represented by a solid lines together with a second dashed line, andrefers to a covalent linkage between two carbon atoms which can beeither a single bond or a double bond. For example, the structure:

can represent either butane or butene.

The term “protecting group” refers to moieties which may be cleaved fromthe compound to yield a hydroxy group, a thiol group, a carboxylic acidgroup, or another functional group which a person of skill in the artdesires to protect. Generally, protecting groups are selected such thatthey resist cleavage during reactions focused on other portions of themolecule. Protecting groups can be selected such that they are acidlabile (e.g., cleavable in the presence of acid), base labile (e.g.,cleavable in the presence of base), or otherwise selectively cleavable.Protecting groups are well known to those of skill in the art. Examplesof suitable protecting groups can be found, for examples in “ProtectiveGroups in Organic Synthesis,” 3^(rd) edition, John Wiley & Sons, Inc.

Examples of protecting groups, include, but are not limited to C₁-C₁₂alkylcarbonyls, C₁-C₆ alkyls, C₁-C₁₅ alkyl silyl moieties (e.g.,moieties which form alkyl silyl ethers when bonded to an adjacentoxygen), aryl(C₁-C₆) alkyls, carbonates, and C₁-C₆ alkoxy-(C₁-C₆)alkyls(e.g., methoxymethyl).

Examples of C₁-C₁₀ alkyl silyl protecting groups include, but are notlimited to, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, or triisopropylsilyl (e.g., trimethylsilyl ether,triethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilylether, or triisopropylsilyl ether when taken together with an adjacentoxygen). Preferably, the alkyl silyl protecting group ist-butyldimethylsilyl ether.

Examples of C₁-C₆ alkyl protecting groups include methyl and t-butyl(e.g., methyl ethers and t-butyl ethers when taken together with anadjacent oxygen).

Examples of aryl (C₁-C₆) alkyl protecting groups include is3,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, or trityl (e.g.,3,4-dimethoxybenzyl ether, p-methoxybenzyl ether, benzyl ether or tritylether when taken together with an adjacent oxygen).

Compounds with two or more groups to be protected (e.g., hydroxy and/orthiol groups) may be protected together using a protecting group whichattaches to both of the hydroxy and/or thiol groups for which protectionis desired. These protecting groups are also referred to herein as“divalent protecting groups.” Examples of divalent protecting groupswhich protect two hydroxy and/or thiol groups include, but are notlimited to C₁-C₆ acetals, C₂-C₆ ketals, and cyclic carbonates. Examplesof cyclic protecting groups include, but are not limited to, acetonide,benzylidine, and, preferably, cyclohexylidine. Examples of protectinggroups which protect two hydroxy and or thiol groups include those shownbelow. The arrows designate where the moiety is attached to the hydroxyor thiol groups on the compound:

The term “acceptable salts” refers to salts of the compounds of theinvention which are acceptable for the methods of the invention, e.g.,the synthesis of intermediates of halichondrin B analogs.

The compounds of the invention that are acidic in nature are capable offorming a wide variety of base salts. The chemical bases that may beused as reagents to prepare acceptable base salts of those compounds ofthe invention that are acidic in nature are those that form base saltswith such compounds. Such base salts include, but are not limited tothose derived from such pharmaceutically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines. The base addition salts of compounds of theinvention that are acidic in nature may be formed with cations byconventional methods.

The term “anti-solvent” includes organic solvents in which the compoundof interest is not substantially soluble in. Examples of anti-solventsfor the compounds of the present invention of formula (II) includenon-polar organic solvents, such as heptane.

The term “alkylating reagent” refers to a reagent which is capable ofadding an alkyl group, preferably a methyl group, to particular organiccompounds described herein including, but not limited to, compounds offormula (Ia). Preferably, the alkylating reagent is a C₁-C₄ alkyl halide(preferably MeI) or a sulfonate.

The term “appropriate alkylating condition” refers to conditions whichare selected such that an alkylating reaction is able to be performed.These conditions include an aprotic solvent (e.g., tetrahydrofuran,toluene, or t-butyl methyl ether) and a base (e.g., a metal amide or ametal alkoxide). Examples of bases which may be used in the alkylatingconditions include, but are not limited to, LDA, KHMDS, and potassiumt-butoxide.

The language “appropriate crystallization conditions” refers toconditions which are selected such that the desired diastereomer of aparticular compound is crystallized, preferably a compound of formula(I) or (Ib). Examples of solvent systems that may be used to performthis crystallization include, but are not limited to, heptane andmixtures of heptane with one or more co-solvents, such as, but notlimited to tert-butyl methyl ether and isopropanol. The ratio of heptaneto tert-butyl methyl ether or isopropanol is selected such that thedesired diastereomer is crystallized. The ratio may range from about 5:1to about 3:1, and is preferably about 4:1. The appropriate conditionsmay also include the addition of a base. Examples of such bases includeC₁-C₆ alkoxides (e.g., t-butyl oxide or isopropoxide). Alternatively,other solvent systems may also be used, such as, combinations of aprotic solvent and an anti-solvent.

The language “second appropriate crystallization conditions” refers toconditions which are selected such that the desired diastereomer of aparticular compound is crystallized, preferably a compound of formula(II) or (IIa). Examples of second appropriate crystallization conditionsfor the crystallization of compounds of formula (II) and/or (IIa)include dissolving the compound in a polar solvent (e.g., MTBE) andoptionally adding an anti-solvent to precipitate the compound.

The term “contacting” refers to any interaction between two or morecompounds which results in a chemical reaction, such as, but not limitedto, the creation or the cleavage of one or more chemical bonds.

The language “mixture of diastereomers” refers to compositions whichcomprise two or more diastereomers.

The term “protic solvent” refers to a solvent which contains adissociable H⁺ or a group capable of forming hydrogen bonds (e.g.,hydroxyl or amine group). Examples are water, methanol, ethanol, formicacid, hydrogen fluoride and ammonia. Preferred protic solvents includealcohols, such as isopropanol.

The language “substantially diastereomerically pure composition” refersto compositions which the ratio of a particular compound to the compoundwith the opposite stereochemistry at the chiral center indicated with anasterisk in Scheme 1 is at least about 8:1 or greater, at least about10:1 or greater, at least about 15:1 or greater, at least about 20:1 orgreater, or, preferably, at least about 30:1 or greater. Diastereomericpurity can be enhanced using multiple kinetic or crystallization induceddynamic resolutions. It also can be enhanced by repeatedrecrystallizations.

The language “substantially no chromatography” refers to methods ofsynthesis which use 4 or fewer, 3 of fewer, 2 or fewer, 1 or fewer, orno chromatography steps. Preferably, the term refers to methods ofsynthesis which do not require preparative HPLC steps.

Certain abbreviations and acronyms are used herein. Definitions forthese abbreviations and acronyms are listed below:

-   ACN Acetonitrile-   AcOH Acetic Acid-   CIDR Crystallization induced dynamic resolution-   DBU Diazabicycloundecane-   DCM Dichloromethane-   DIBAL Diisobutylaluminium hydride-   DME Dimethoxyethane-   DMF Dimethylformamide-   ESI Electron spin injection-   Et₃N Triethylamine-   EtOAc Ethyl acetate-   EtOH Ethanol-   FDA Food and Drug Administration-   HPLC High pressure liquid chromatography-   IPA Isopropanol-   ^(i)Pr₂NEt Diisopropylethylamine-   KHMDS Potassium-Hexamethyldisilazane-   KO^(t)Bu Potassium tert-butoxide-   LDA Lithium diisopropyl amide-   LRMS Low resolution mass spectrometry-   MeI Methyl iodide-   MeOH Methanol-   MsCl Mesyl chloride (methanesulfonyl chloride; CH₃SO₂Cl)-   MTBE Methyl tert-butyl ether-   MsO— Mesylate (methanesulfonate)-   NaOEt Sodium ethoxide-   NaOMe Sodium methoxide-   NBS N-bromosuccinimide-   NIS N-iodosuccinimide-   NMR Nuclear magnetic resonance-   Ph₃P Triphenyl phosphine-   TBDPSCl tert-Butyl diphenyl silyl chloride-   TBME tert-Butyl methyl ether-   TBS tert-Butyldimethyl silyl-   TBSCl tert-Butyldimethyl silyl chloride-   TBSOTf tert-Butyldimethylsilyl trifluoromethanesulphonate-   ^(t)BuOK Potassium tert-butoxide-   TEA Triethylamine-   TESOTf Triethylsilyl trifluoromethanesulfonate-   TsCl Tosyl chloride (p-toluenesulfonyl chloride)-   TfO— Triflate (trifluoromethanesulfonate)-   Tf₂O Triflic anhydride (CF₃SO₂)₂O-   TsO— Tosylate (p-toluenesulfonate)-   THF Tetrahydrofuran-   TsOH p-Toluene sulfonic acid-   TosMIC Toluenesulfonylmethyl isocyanide-   Trt Trityl (Triphenylmethyl)

B. Compounds

In one embodiment, the invention pertains to a compound of formula (I):

wherein:

z is a single or double bond, provided that when z is a double bond, X²is C and Y¹ is hydrogen; and provided that when z is single bond, X² isCH or O;

X¹ is O, S, or CN, provided that when X¹ is CN or S, X² is O;

Y¹ is a halide, hydrogen or O-L², or absent when X² is O; and

L¹ and L² are independently selected from hydrogen and a protectinggroup, or L¹ and L² together are a protecting group, provided that whenX¹ is CN, L¹ is absent; and salts thereof. The invention also pertainsto compounds of formula (I).

In an embodiment, L¹ and/or L² are each independently a silyl ether, aC₁-C₈ alkyl ether, an acyl (—C(═O)CH₃), or acetyl group. Preferably, X¹is oxygen.

Preferably, L¹ and L² may represent the same protecting group attachedto the molecule through both the O of X² when Y¹ is O-L² and X¹.Examples of such protecting groups include, but are not limited to,cyclic C₁-C₆ acetals, cyclic C₂-C₆ ketals, and cyclic carbonates. In afurther embodiment, L¹ and L² are linked to a single divalent protectinggroup. Examples of divalent protecting groups include acetonides,benzylidines, and preferably, cyclohexylidine. In certain embodiments,when both L¹ and L² are protecting groups, L¹ and L² when taken togethermay form a pentane, hexane, or pyran ring and link to X¹ to X² through asingle carbon atom. Preferably, when Y¹ is O-L²; X¹ is O or S; L¹ and L²together form protecting group which is a C₄-C₇ alkyl ring with onemember of the ring covalently linked to the O of O-L² and to X¹.

In one embodiment, X² is CH, Y¹ is O-L², and X¹ is O.

In another embodiment, when Y¹ is a halide, it is fluoride, chloride,iodide, or, preferably, bromide. In another further embodiment, L¹ isacetyl.

In another embodiment, when z is a double bond, Y is hydrogen, and X² isC. In another further embodiment, X¹ is oxygen and L¹ is a protectinggroup (when taken together with X¹) selected from the group consistingof C₁-C₆ alkyl ether, aryl (C₁-C₆) alkyl ether, C₁-C₆ ester, and a silyl(C₁-C₁₀) ether.

In another further embodiment, X² is oxygen, when z is a single bond. Inanother further embodiment, L¹ is hydrogen. In another furtherembodiment, L¹ is a protecting group selected from a glycoside, C₁-C₆alkyl, C₁-C₆ acetyl, and a C₁-C₆ ester.

Preferably, the compound of formula (I) is a compound of formula (Ib):

wherein L^(1a) and L^(1b) are hydrogen, independently selectedprotecting groups, or together a single divalent protecting group.

In a further embodiment, L^(1a) and L^(1b) are each protecting groupsselected from C₁-C₆ alkyl ethers, aryl (C₁-C₆) alkyl ethers, silyl(C₁-C₁₀) ethers, C₁-C₆ alkyl esters, cyclic C₁-C₆ acetals, cyclic C₂-C₇ketals, and cyclic carbonates.

In a further embodiment, the invention pertains to a compositioncomprising a compound of formula (Ib), wherein the composition issubstantially diastereomerically pure. In a further embodiment, theratio of compounds of formula (Ib) to the compounds with the oppositestereochemistry at the chiral center marked with the asterisk is atleast about 8:1 or greater, at least about 20:1 or greater, or,preferably, at least about 30:1 or greater.

In a further embodiment, the compound of formula (I) is selected fromthe group consisting of:

or a salt thereof.

In another embodiment, the invention pertains to a compound of formula(II):

wherein:

c is a single or double bond, provided that when c is a double bond m isO and Y³ is O or CHCO₂-L³, and provided that when c is a single bond mis 0 or 1 Y³ is CH₂O-L³, CH₂CO₂-L³ or CH₂CH₂O-L³;

Y² is C₁-C₇ sulfonate, O-L⁴ or a halide;

L⁴ is hydrogen or a protecting group; and

L³ and L⁵ are each independently hydrogen or a protecting group, or L³and L⁵ together are a protecting group, or a salt thereof.

Examples of Y² include halides, e.g., fluoride, chloride, bromide, orpreferably, iodide. In another embodiment, Y² is O-L⁴. Examples of L⁴include hydrogen. In another embodiment, c is a double bond. Examples ofY³ when c is a double bond include CHCO₂-L³. Examples of L³ groupsinclude C₁-C₆ alkyl, e.g., methyl.

In another embodiment, c is a single bond. Examples of Y³ when c is asingle bond include CH₂CH₂—OL³. In a further embodiment, L³ and L⁵ maybe linked to form a cyclic C₁-C₆ acetal or a cyclic C₂-C₇ ketal.

In a further embodiment, Y³ is CH₂CO₂-L³ and L³ is C₁-C₁₀ alkyl, C₄-C₁₀aryl-C₁-C₆ alkyl, or C₄-C₁₀ aryl. In another further embodiment, Y² is ahalide, e.g., iodide.

In a further embodiment, the invention pertains to a compositioncomprising a compound of formula (II), wherein the composition issubstantially diastereomerically pure. In a further embodiment, theratio of compounds of formula (II) to the compounds with the oppositestereochemistry at the chiral center marked with the asterisk is atleast about 8:1 or greater, at least about 20:1 or greater, or,preferably, at least about 30:1 or greater.

In another further embodiment, the compound of formula (II) is selectedfrom the group consisting of:

or a salt thereof.

The invention also pertains to compositions comprising the compoundsshown above substantially free of diastereomers.

In a further embodiment, the invention also pertains to a compound offormula (IIa):

In a further embodiment, the compound of formula (IIa) is substantiallyfree of diastereomers, e.g., a compound with the oppositestereochemistry at the chiral carbon indicated with an asterisk in theformula above. In an embodiment, the invention pertains to asubstantially diastereomerically pure composition comprising a compoundof formula (IIa), wherein the ratio of compounds of formula (IIa) tocompounds with the opposite stereochemistry at the chiral center markedwith the asterisk is at least about 8:1 or greater, at least about 20:1or greater, or, preferably, at least about 30:1 or greater.

The compound of formula (IIa) is particularly important because while itis crystalline, the corresponding non-methylated intermediate is notcrystalline and requires purification via chromatography. The inventionalso pertains to a compounds of formula (IIa) in crystalline form.

In another embodiment, the invention pertains to a compound of formula(III):

wherein: L⁶ is hydrogen or a protecting group; or an acceptable saltthereof. In an embodiment, the invention pertains to a substantiallydiastereomerically pure composition comprising a compound of formula(III), wherein the ratio of compounds of formula (III) to compounds withthe opposite stereochemistry at the chiral center marked with theasterisk is at least about 8:1 or greater, at least about 20:1 orgreater, or, preferably, at least about 30:1 or greater.

In a further embodiment L⁶ is hydrogen or, when taken together with theoxygen to which it is bound, a silyl C₁-C₁₀ ether. Examples of suchsilyl C₁-C₁₀ ethers include, but are not limited to, trimethylsilylether, triethylsilyl ether, t-butyldimethylsilyl ether,t-butyldiphenylsilyl ether, or triisopropylsilyl ether.

In a further embodiment, the compound of formula (III) is:

The invention also pertains to compositions comprising the compoundsshown above substantially free of diastereomers.

In another embodiment, the invention pertains to compounds of formula(IIIa):

wherein L^(6a), L^(6b), and L^(6c) are each protecting groups, or a saltthereof. In a further embodiment, the invention pertains to acomposition comprising the compound of formula (IIIa) wherein thecomposition is substantially free of diastereomers (e.g., compounds withthe opposite stereochemistry at the chiral center indicated with anasterisk in formula (IIIa) above).

The invention also pertains, at least in part, to compounds of formula(Id):

wherein L^(1a) and L^(1b) are independently selected from hydrogen and aprotecting group, or L^(1a) and L^(1b) together are a divalentprotecting group, or a salt thereof.

C. Methods

In one embodiment, the invention pertains to a method of obtaining asubstantially diastereomerically pure composition comprising a compoundof formula (I). The method includes crystallizing the compound offormula (I) from a mixture of diastereomers under appropriatecrystallization conditions, such that a substantially diastereomericallypure composition comprising a compound of formula (I) is formed.

The mixture of diastereomers is preferably a mixture of compounds offormula (I) with compounds of formula (Ie), wherein said compounds offormula (Ie) is:

In one embodiment, the substantially diastereomerically pure compositioncomprises a ratio of compounds of formula (I) to compounds of formula(Ie) of at least about 8:1 or greater, of at least about 10:1 orgreater, of at least about 20:1 or greater, or, preferably, at leastabout 30:1 or greater. In order to increase the diastereomeric purity ofthe compound of formula (I), additional recrystallizations of thecompound under similar appropriate conditions may be conducted.

The appropriate crystallization conditions are selected such that thedesired diastereomer is crystallized. Examples of solvent systems thatmay be used to perform this crystallization include, but are not limitedto, heptane/tert-butyl methyl ether and heptane/isopropanol. Theappropriate conditions may also include the addition of a base. Examplesof such bases include C₁-C₆ alkoxides (e.g., t-butyl oxide orisopropoxide).

Alternatively, other solvent systems may also be used, such as,combinations of a protic solvent (e.g., an alcohol, e.g., isopropanol)and an anti-solvent (e.g., non-polar organic solvent, e.g., heptane).

In a further embodiment, the invention also pertains to a method ofsynthesizing the compound of formula (Ib) from a compound of formula(Ia) by contacting a compound of formula (Ia) with an alkylating reagentunder appropriate alkylating conditions. The compound of formula (Ia)is:

and the compound of formula (Ib) is:

wherein L^(1a) and L^(1b) are independently selected from hydrogen and aprotecting group, or L^(1a) and L^(1b) together are a divalentprotecting group, provided that L^(1a) of formulae (Ia) and (Ib) are thesame and L^(1b) of formulae (Ia) and (Ib) are the same. The methodincludes reacting the compound of formula (Ia) under alkylatingconditions to form a mixture comprising the compound of formula (Ib) anddiastereomers thereof; and crystallizing the compound of formula (Ib)from the mixture, under appropriate crystallization conditions.

In order to increase the diastereomeric purity of the compound offormula (Ib), additional recrystallizations of the compound undersimilar appropriate conditions may be conducted. Preferably, the mixtureof diastereomers after two or more crystallizations results in a ratioof compounds of formula (Ib) to compounds with the oppositestereochemistry around the chiral center indicated with the asteriskabove in formula (Ib) to be at least about 8:1 or greater, at leastabout 10:1 or greater, at least about 20:1 or greater, or at least about30:1 or greater.

In yet another embodiment, the invention also pertains, at least inpart, to a method of obtaining a substantially diastereomerically purecomposition comprising a compound of formula (I). The method includescontacting a mixture of diastereomers with a base at an appropriatetemperature, such that a substantially diastereomerically purecomposition comprising a compound of formula (I) is formed.

Examples of bases which may be used in the method include bases known inthe art, such as amide bases, metal alkoxides and KHMDS. The base may bepresent in any amount such that the desired diastereomer is formed.Preferably, the base is present in sub stoichiometric amounts (e.g.,less than one equivalent). In another further embodiment, theappropriate temperature is less than about −30° C. In a furtherembodiment, the compound of formula (I) is a compound of formula (Ib).

If kinetic resolution of the stereocenter is desired, the compound offormula (I) or (II) may be treated with sub-stoichiometric amounts of astrong base (e.g., an amide base, e.g., KHMDS) at low temperatures(e.g., less than about −30° C.). Once the reaction has taken place,compounds of formula (I) or (II) may be isolated from an appropriatecrystallization solvent system and recrystallized. Examples of solventsystems which may be used include, but are not limited to, heptane,heptane/t-butyl methyl ether and heptane/isopropanol.

Alternatively, crystallization induced dynamic resolution (CIDR) mayalso be used to enhance the diastereomeric purity of compounds offormula (I) and/or (II). For example, compounds of formula (I) and/or(II) may be treated with a weak base, such as an alkoxide, (e.g.,potassium t-butyl oxide or potassium isopropoxide) in an appropriatecrystallization solvent system. Examples of appropriate crystallizationsolvent systems include combinations of a protic solvent (e.g.,isopropanol) and an anti-solvent (e.g., heptane) at non-cryogenictemperatures to provide purified compounds of formula (I) or (II).

In another embodiment, the invention pertains to a method of obtaining asubstantially diastereomerically pure composition comprising a compoundof formula (II). The method includes crystallizing the compound offormula (II) from a mixture of diastereomers under appropriatecrystallization conditions, such that a substantially diastereomericallypure composition comprising a compound of formula (II) is formed.

In one embodiment, the composition comprises a ratio of compounds offormula (II) to compounds of formula (IIb) of at least about 8:1 orgreater, at least about 10:1 or greater, at least about 20:1 or greater,or, preferably, at least about 30:1 or greater. The compound of formula(IIb) is:

In order to increase the diastereomeric purity of the compound offormula (II), additional recrystallizations of the compound undersimilar appropriate conditions may be conducted.

In another embodiment, the invention also pertains to a method ofsynthesizing a compound of formula (IIa) from a compound of formula(Ib). The method includes selectively crystallizing a compound offormula (Ib) under appropriate crystallization conditions; and reactingthe compound of formula (Ib), under appropriate conditions, such that acompound of formula (IIa) is formed. Preferably, the compound of formula(IIa) is formed using substantially no chromatography. The compound offormula (Ib) may be reacted under appropriate conditions to form acompound of formula (IIa), after having had been diastereomericallypurified using recrystallization. Furthermore, the appropriateconditions may comprise dissolving a crystallized compound of formula(Ib) in a solvent before reacting it under appropriate conditions toform a compound of formula (IIa).

Appropriate conditions for the synthesis of compounds of formula (IIa)from compounds of formula (Ib) are described, for example, in Schemes 5,6, 8, 9, and 10. Methods for selectively crystallizing a compound offormula (I) or (Ib) from a mixture of diastereomers under appropriatecrystallization conditions has been described above.

The invention also pertains, at least in part, to a method ofsynthesizing a compound of formula (IIIa) from a compound of formula(IIa). The method includes crystallizing a compound of formula (IIa)under second appropriate crystallization conditions; reacting thecompound of formula (IIa) under appropriate conditions such that acompound of formula (IIIa) is formed.

Examples of second appropriate crystallization conditions for thecrystallization of compounds of formula (IIa) include dissolving thecompound in a polar solvent (e.g., MTBE) and optionally adding ananti-solvent to precipitate the compound. Examples of anti-solventswhich may be used include heptane. Preferably, the compound of formula(IIa) is reacted under appropriate conditions to form a compound offormula (IIIa), after having had been crystallized.

In another embodiment, the invention also pertains to a method ofsynthesizing a compound of formula (IIIa) from a compound of formula(Ib). The method includes selectively crystallizing a compound offormula (Ib) under appropriate crystallization conditions; and reactingthe compound of formula (Ib) under appropriate conditions such that acompound of formula (IIIa) is formed. Preferably, the compound offormula (IIIa) is formed using substantially no chromatography.

The compound of formula (Ib) may be reacted under appropriate conditionsto form a compound of formula (IIIa), after having had beendiastereomerically purified using recrystallization. Furthermore, theappropriate conditions may comprise dissolving a crystallized compoundof formula (Ib) in a solvent before reacting it under appropriateconditions to form a compound of formula (IIIa).

In another embodiment, the invention pertains to a method ofsynthesizing compounds of formula (IV). The method includescrystallizing a compound of formula (Ib) from a mixture of diastereomersunder appropriate crystallization conditions, as described above;reacting the selectively crystallized compound of formula (Ib) withappropriate reagents, such that a compound of formula (IV) issynthesized. The compound of formula (IV) is:

wherein each of L^(7a), L^(7b), L^(7c), L^(7d), and L^(7e) are each aprotecting group or hydrogen. Examples of L^(7a) include phenyl.Examples of L^(7b) include methyl. Examples of L^(7c) and L^(7d) includeTBS. Examples of L^(7e) includes hydrogen.

Examples of appropriate reagents which may be used to synthesizecompounds of formula (IV) from a compound of formula (Ib) include thosedescribed in Schemes 5, 6, 8, and 9 to form a compound of formula(IIIa). Methods which may be used to convert a compound of formula(IIIa) to a compound of formula (IV) are described in greater detail inWO/2005/118565, incorporated herein by reference in its entirety.

The compound of formula (Ib) may be reacted under appropriate conditionsto form a compound of formula (IV), after having had beendiastereomerically purified using recrystallization. Furthermore, theappropriate conditions may comprise dissolving a crystallized compoundof formula (Ib) in a solvent before reacting it under appropriateconditions to form a compound of formula (IV).

In a further embodiment, the compound of formula (IV) is formed ingreater than about 50% yield, greater than about 60% yield, or greaterthan about 70% yield from a compound of formula (Ib).

In a further embodiment, the invention also pertains to compounds offormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III),(IIIa), (IV), (V), or otherwise described herein. The invention alsopertains to compositions comprising compounds of any one of theseformulae, substantially free of diastereomers. The invention alsopertains to each of the intermediates and processes described herein.

In a further embodiment, the invention pertains to compositionscomprising the compounds described herein substantially free ofdiastereomers, e.g., compounds with the opposite stereochemistry at thechiral carbon indicated with the asterisk in Scheme 1. The inventionalso pertains to methods of using these compounds to synthesizecompounds of formula (IV), B-1939, or other halichondrin B analogs.

The invention pertains, at least in part, to methods and intermediatesfor the conversion of compounds of formula (I) to compounds of formula(III). Compounds of formula (III) may further be converted to compoundsof formula (IV) and/or halichondrin B or analogs thereof.

The compounds of formula (III) can be synthesized by methods describedherein. The invention pertains, at least in part, to all compounds andintermediates described herein and the processes of synthesizing thecompounds and intermediates.

Conversion of Compound 2-1 to a Compound of Formula (Ib)

Compounds of formula (Ib) can be synthesized from compounds of formula2-1, as shown in Scheme 2:

Compound 2-1 may be converted to compound (Ib). In Scheme 2, L^(1a) andL^(1b) are protecting groups. Examples of protecting groups include, butare not limited to C₁-C₆ alkyl ethers, aryl (C₁-C₆) alkyl ethers, silyl(C₁-C₁₀) ethers, C₁-C₆ alkyl esters, cyclic C₁-C₆ acetals, cyclic C₂-C₇ketals, and cyclic carbonates. Examples of R² include hydrogen, C₁-C₆alkyl (e.g., methyl, t-butyl, etc.), C₄-C₁₀ aryl (e.g., phenyl), andC₄-C₁₀ aryl-C₁-C₆ alkyl groups (e.g., benzyl). Examples of R³ and R⁴include CH₃ and OCH₃, respectively, or R³ and R⁴ taken together can be(—CH₂CH₂)₂O.

Compound 2-1 can be converted to compound 2-4 through the use of anappropriate reducing agent. Examples of such reducing agents include,but are not limited to, aluminum hydrides and borohydrides (e.g. BH₃,AlH₃, LiBH₄, LiAlH₄, NaBH₄, NaAlH₄, ZnBH₄).

The hydroxyl group of compound 2-4 may be transformed to a leaving groupsuch as but not limited to a sulfonate (e.g., MsO—, TsO—, TfO—) orhalide by methods described in the literature. Subsequent treatment witha cyanide source (e.g., KCN or NaCN) results in the formation ofcompound 2-5.

Alternatively, compound 2-4 may be transformed to compound 2-5 byoxidation of the hydroxyl group to the aldehyde by methods described inthe literature. Conversion of the aldehyde to the nitrile may beachieved with appropriate reagents such as, but not limited to, dimethylphosphorocyanidate/samarium iodide. Compound 2-5 may be alkylated in anappropriate solvent, e.g., an aprotic solvent such as tetrahydrofuran,toluene, TBME and subsequently treated with a strong base such as ametal amide or metal alkoxides (e.g., LDA, KHMDS, or KO^(t)Bu) and anappropriate alkyl halide (e.g., X-Me) or sulfonate to provide a compoundof formula (Ib).

Alternatively, compound 2-1 may be converted to compound 2-7 by methodsknown in the art. Examples of such methods include, but not limited to,treatment with N,O-dimethylhydroxylaminehydrochloride/trimethylaluminum. Compound 2-7 can be converted into thecompound of formula (Id), by treatment with an appropriatecarbon-nucleophile. Examples of such nucleophiles include, but are notlimited to, alkyl Grignard reagents.

Alternatively, oxidation of compound 2-4 to the aldehyde followed byaddition of an alkyl Grignard or other carbon-nucleophile provides asecondary alcohol. Oxidation using known methods results in theformation of the compound of formula (Id). Compounds of formula (Ib) maybe synthesized, for example, by the treatment of the compound of formula(Id) with TosMIC in the presence of metal alkoxides, such as NaOEt andKOtBu (J. Org. Chem. 42(19), 3114-3118, (1977)). Alternatively, thecompound of formula (Id) may be transformed to the compound of formula(Ib) using reagents such as but not limited to dimethylphosphorocyanidate/samarium iodide.

Conversion of (−)-Quinic Acid to a Compound of Formula (Id)

Alternatively a compound of formula (Id) may also be synthesized asshown in Scheme 3.

In Scheme 3, L^(1a) and L^(1b) are protecting groups, as described inScheme 2. L^(2b) and L^(2c) are also protecting groups such as, but notlimited to, cyclic acetals (X═O and/or S), cyclic ketals (X═O and/or S),and cyclic carbonates (X═O).

The synthesis of compound 3-9 from commercially available (−)-quinicacid has been described previously (WO/2005/118565). Compound 3-9 may bereduced with DIBAL or other reagents known in the art, such as aluminumhydrides and borohydrides, to provide lactol 3-10. The lactol 3-10 canbe transformed using a Wittig or Julia olefination to provide compound3-11. Deprotection followed by double bond migration and Michaeladdition generate compound (Id).

More specifically, a Wittig olefination may be carried out usingMeC(OL^(2b))(OL^(2c))CH₂CH₂PPh₃ (prepared in situ), in a polar solvent(e.g., THF, MeOH, or DMF) at a temperature ranging from 0° C. to 50° C.Acid-catalyzed sequential reactions (e.g., deprotection, migration, andMichael addition) may be carried out with an acid such as TsOH or HCl ina polar solvent (e.g. THF, or acetone) at a temperature ranging from 10to 30° C. for about two to four hours. Alternatively, the migration andMichael addition may also be carried out with a base such as NaOMe in apolar solvent (e.g., THF or MeOH).

Conversion of Compound 4-1 to a Compound of Formula (I)

As shown in Scheme 4, compounds of formula 4-1 (diastereomeric mix) mayundergo isomerization and crystallization to provide compounds offormula (I).

In Scheme 4, z is a single or double bond, provided that when z is adouble bond, X² is C and Y¹ is hydrogen; and provided that when z issingle bond, X² is CH or O; X¹ is O, S, or CN, provided that when X¹ isCN or S, X² is O; Y¹ is a halide, hydrogen or O-L², or absent when X² isO; and L¹ and L² are independently selected from hydrogen and aprotecting group, or L¹ and L² together are a protecting group, providedthat when X¹ is CN, L¹ is absent.

Diastereomers of formula 4-1 may be converted to compounds of formula(I) via treatment with sub-stoichiometric amounts of amide bases (e.g.,KHMDS) at low temperatures (e.g., less than about −30° C.). Oncequenched, compounds of formula (I) may be isolated and recrystallizedfrom a suitable crystallization solvent systems, such as, but notlimited to, heptane/t-butyl methyl ether and heptane/isopropanol.

Alternatively a crystallization induced dynamic resolution (CIDR) mayalso be used to selectively crystallize compounds of formula (I). Forexample, diastereomers of formula 4-1 may be treated with a base, suchas an alkoxide, (e.g., t-butyl oxide or isopropoxide) in an appropriatecrystallization solvent system. Examples of appropriate crystallizationsolvent systems include combinations of a protic solvent (e.g.,isopropanol) and an anti-solvent (e.g., heptane) at non-cryogenictemperatures to provide purified compounds of formula (I).

Conversion of a Compound of Formula (Ib) to Compound 5-13

In Scheme 5, L^(1a) and L^(1b) are as described above in Scheme 2.L^(1d) is a suitable protecting group, e.g., C₁-C₆ alkyl ether, aryl(C₁-C₆) alkyl ether, C₁-C₆ ester, or a silyl (C₁-C₁₀) ether.

Compounds of formula (Ib) may be deprotected by various methods known inthe art, depending on the nature of L^(1a) and L^(1b). Examples ofdeprotecting reactions include, but are not limited to hydrogenation,reduction, oxidation, base induced deprotection, and acid induceddeprotection. One of ordinary skill in the art would be able to choosean appropriate technique based on art recognized techniques (see, e.g.,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley &Sons, Inc).

Once L^(1a) and L^(1b) have been removed, the deprotected compound 5-12may be converted to compound 5-13 by treatment of compound 5-12 with2-acetoxy-2-methylpropionyl bromide, catalytic water, in a polar aproticsolvent such as acetonitrile. The resulting intermediate may be treatedwith a base (e.g., diazabicycloundecane (DBU)) to provide compound 5-13.

Alternatively, compound 5-12 may be transformed to compound 5-13 using amulti-step process. The process involves selectively activating of onehydroxyl group as a halide, MsO—, TsO—, or TfO— and protecting of theremaining hydroxyl group. Examples of suitable protecting groups forthis step include L^(1d) groups such as C₁-C₆ alkyl ethers, aryl (C₁-C₆)alkyl ethers, C₁-C₆ esters, and silyl (C₁-C₁₀) ethers. The intermediatecan be transformed to compound 5-13 using methods described previously.

Conversion of Compound 5-13 to Compound 6-16

In Scheme 6, L^(1d) is hydrogen or a protecting group, C₁-C₆ alkylether, aryl (C₁-C₆) alkyl ether, C₁-C₆ ester, or a silyl (C₁-C₁₀)ether). L^(1c) may be hydrogen or a protecting group, such as, but notlimited to a glycoside, C₁-C₆ alkyl, or a C₁-C₆ ester. X² and X³ mayeach be oxygen or hydroxy.

Oxidative cleavage of the olefin of compound 5-13 may be accomplishedusing ozone in a suitable solvent (e.g., methanol) at temperatures below0° C. The ozone adduct may worked up using literature methods to providecompound 6-14, wherein X² and X³ are each carbonyl or hydroxy.Alternatively, a metal oxide (e.g., osmium tetroxide or potassiumpermanganate and sodium periodate) may also be used to provide compound6-14, wherein X² and X³ are each carbonyl.

When X² and X³ are each carbonyl, they can be reduced to providecompound 6-14, wherein X² and X³ are each hydroxy. Deprotection of L¹may be achieved using literature methods (e.g., potassium carbonate inmethanol) to provide compound 6-15. Compound 6-15 may be treated withNaIO₄ to provide compound 6-16, wherein L^(1c) is H. Alternatively,compound 6-16 may comprise a glycoside (e.g., L^(1c) is C₁-C₃ alkyl,e.g., methyl) protecting group which can be added using methods known inthe art, such as methanol in the presence of an acid catalyst.

Conversion of Compound 2-1 to Compound 6-16

In Scheme 7, an alternate route to compound 6-16 is shown. Examples ofR² include hydrogen, C₁-C₆ alkyl (e.g., methyl, t-butyl, etc.), C₄-C₁₀aryl (e.g., phenyl), and C₄-C₁₀ aryl-C₁-C₆ alkyl groups (e.g., benzyl).L^(1a) and L^(1b) are protecting groups as described above. Examples ofL^(1c) include hydrogen and protecting groups such as glycosides, C₁-C₆alkyl and C₁-C₆ acetyl.

Compound 2-1 may be transformed to compound 7-17d as described inSchemes 5 and 6. Treatment of compound 7-17d with TosMIC andisomerization/crystallization provides compound 6-16, as shown inSchemes 2 and 4.

Conversion of Compound 5-16 to Compound 7-20

Compound 8-20 may be prepared from 6-16 as shown in Scheme 8. In Scheme8, L^(1c) is hydrogen or a protecting group as described previously; L⁵is C₁-C₁₀ alkyl, C₄-C₁₀ aryl-C₁-C₆ alkyl, or C₄-C₁₀ aryl; and Y² issulfonate or halide.

When L^(1c) is not hydrogen, the ether is hydrolyzed using literaturemethods to provide lactol (6-16, L^(1c)═H). The lactol (6-16, L^(1c)═H)is converted to compound 8-18 by an olefination reaction such as astabilized Wittig reaction, a Wadsworth-Homer-Emmons reaction, or aJulia olefination. The Wittig olefination may be carried out with astabilized ylide such as Ph₃PCHCO₂L⁵ in polar solvent (e.g., THF, MeOH,or DMF) at an appropriate temperature (e.g., −78° C. to 50° C.). TheWadsworth-Horner-Emmons olefination may be carried out using astabilized ylide (e.g. (MeO)₂POCH₂CO₂L⁵) in a polar aprotic solvent(e.g., THF, or ACN) at an appropriate temperature (e.g., −78° C. to 25°C.) in the presence of a suitable base (e.g., ^(t)BuOK, NaH, orLiCl/tertiary amines (e.g. DBU, ^(i)Pr₂NEt, Et₃N)).

Variations on these conditions are known in the art. For example, forvariations on the Wadsworth-Horner-Emmons olefination see Org. React.25, 73-253, (1977) and Tetrahedron Lett. 25, 2183 (1984). Furthermore,the Julia olefination may be carried out in a polar aprotic solvent(e.g., THF, DME or a halogenated solvent, e.g., CH₂Cl₂) in the presenceof alkyl sulfone (e.g., alkyl(benzothiazol-2-ylsulfonyl)acetate) andsuitable base (e.g., BuLi, LDA, KHMDS, or DBU) at an appropriatetemperature (e.g., −78° C. to 25° C.). Variations on these conditionswill be apparent from the literature on Julia olefination (see, Org.Biomol. Chem. 3, 1365-1368, (2005); Synlett, 26-28, (1998)).

Compound 8-19 can be obtained from compound 8-18 via catalytichydrogenation, which may be carried out in the presence of a metalcatalyst (e.g., palladium (Pd/C) or platinum (PtO₂)) in a polar solvent(e.g. EtOAc, MeOH). Preferably, the reaction is carried out under ahydrogen atmosphere, with a pressure ranging from 0.04 bar to 1.10 bar.

The hydroxyl group of 8-19 may be converted to a leaving group (e.g.,MsO—, TsO—, TfO—) providing 8-20, using a suitable sulfonyl anhydride orsulfonyl chloride (e.g., MsCl, TsCl, or Tf₂O) in a polar aprotic solvent(e.g., THF or a halogenated solvent (e.g., CH₂C₁₂)), in the presence ofa suitable base (e.g., Et₃N).

Optionally, the leaving group of 8-20 may be converted to a halide. Thisreaction may be carried out in the presence of a halogenating reagent(e.g., NaI, or NaBr) in a polar solvent (e.g., DMF or acetone).Alternatively, the transformation of hydroxyl group to halide may becarried out using a halogenating reagent (e.g., NIS, or NBS) in a polarsolvent (e.g., THF) in the presence of Ph₃P and a suitable base such aspyridine.

Conversion of Compound 6-15 to Compound 8-20

In Scheme 9, another method of converting compound 6-15 to compound 8-20is shown. In Scheme 9, R^(9a) and R^(9b) are hydrogen, C₁-C₆ alkyl ortaken together are a carbonyl group; Y² is sulfonate or halide; and Y³is O, OL³, or CHCO₂-L₃ wherein L³ is hydrogen or a protecting group.

As shown in Scheme 9, compound 8-20 can be prepared from compound 6-15using literature methodology for the protection of 1,2 diols. Treatmentof the neopentyl-hydroxyl of compound 9-21 (using methods described inScheme 8) provides compound 9-22. Deprotection of the compound 9-22using literature methods provides a diol. Treatment of this diol with areagent such as sodium periodate provides aldehyde 9-23 (Y³═O).Treatment of the aldehyde 9-23 as described in Scheme 8 providescompound 8-20.

Conversion of Compound 7-17b to 8-20

Alternatively, compound 7-17b may be converted to compound 8-20 as shownin Scheme 10. In Scheme 10, R² includes C₁-C₆ alkyl such as methyl,ethyl, and tert-butyl; R^(10a) and R^(10b) are hydrogen, C₁-C₆ alkyl ortaken together are a carbonyl group; Y² is sulfonate or halide; and Y³is O, OL³, or CHCO₂-L₃. L³ is hydrogen or a protecting group.

Compound 7-17b may be transformed into compound 10-17f by selectivelyprotection of the 1,2-diol and a subsequent functional grouptransformation of the neopentyl hydroxyl group to a sulfonate or halide.Selective protection of 1,2-diol may be carried out with an aldehyde,ketone, acetal, or a carboxyl chloride (e.g. DMP, cyclohexanone,MeOPhCHO, or Ph₃P) in the presence of acid catalyst. The functionalgroup transformation of the neopentyl hydroxyl group to a sulfonate orhalide has been previously described above in Scheme 8. Compound 10-17gand 10-22 may be prepared in a similar manner previously described inScheme 2. Deprotection of the diol protecting group using literatureprocedures followed by treatment with sodium periodate provides 10-23(Y═O). A Wittig, Horner-Wadsworth-Emmons, or Peterson type olefinationis then followed with hydrogenation to provide compound 8-20.

D. Chemical Examples Example 1: Synthesis of Compound AD from CompoundAC

Compound AC (1 Wt, 1 V, 1 eq) was dissolved in THF (1.80 V) and cooledto −75° C. KHMDS (0.50 M solution in toluene, 6.60 V, 1.10 eq) was addedat a rate such that internal temperature did not exceed −65° C. Uponcomplete addition, stirring was continued at −75° C. for 30 minutes. Asolution of MeI (0.188 V, 1.01 eq) in THF (0.50 V) was added at a ratesuch that internal temperature did not exceed −65° C. Upon completeaddition, stirring was continued at −75° C. for 1 hour. KHMDS (0.50 Msolution in toluene, 0.60 V, 0.10 eq) was added at a rate such thatinternal temperature did not exceed −70° C. and stirring was continuedat −75° C. for additional 2.5 hours. Under vigorous stirring, 20 wt %NH₄Cl aq (1.50 Wt, 1.9 eq) was added at a rate such that internaltemperature did not exceed −55° C. Upon complete addition, the resultantmixture was allowed to warm to −20° C. Water (1.50 V) was added and themixture was further warmed to 0° C. The biphasic mixture was transferredto a work-up vessel (the reactor was washed with MTBE (0.40 V)) andvigorous stirring was continued for 2 minutes. The aqueous layer was setaside and the organic layer was washed with water (2.0 V). The organiclayer was concentrated and residual solvents and water wereazeotropically removed with heptane (1.50 V×2) to give the crude productas a yellow solid (1.1 Wt, dr=4.4:1).

The crude (1.1 Wt) was suspended in heptane-MTBE (4:1 v/v, 5.0 V) andheated to 80° C. The resultant solution was: 1) cooled to 70° C. over 1hour; 2) held at 70° C. for 0.5 hour; 3) cooled to 65° C. over 0.5 hour(precipitation started); 4) held at 65° C. for 0.5 hour; 5) cooled to60° C. over 0.5 hour; 6) held at 50° C. for 0.5 hour; 7) cooled to roomtemperature and stirring was continued for 40 hours. Crystals werecollected by filtration, washed with heptane (1 V×2) and dried underN₂/vacuum to give Compound AD as light tan powder (0.69 Wt, 0.66 eq,dr=34:1). The mother liquor was concentrated to give an epimeric mixture(Compound AS) as yellow solid (epimeric mixture, 0.38 Wt, dr CompoundAD: epimer=1:2.2).

Example 2: Diastereomeric Purification of Compound AD from Compound AS

Each of the following methods was used in the reaction shown in Scheme12 to convert the undesired C25 epimer to the desired C25 isomer, usingeither stereoselective deprotonation-protonation or crystallizationinduced dynamic resolution (CIDR).

Method 1: Compound AS (1 Wt, 1 V, dr=1:2.2) was dissolved in toluene(2.6 V) and cooled to −20° C. KHMDS (0.50 M solution in toluene, 3.4 V,0.60 eq) was added at a rate such that internal temperature did notexceed −16° C. Upon complete addition, stirring was continued at −20° C.for 15 minutes. Under vigorous stirring, 20 wt % NH₄Cl aq (1.0 Wt, 1.3eq) was added at a rate such that internal temperature did not exceed−15° C. After 5 minutes, the mixture was allowed to warm to 0° C. Theorganic layer was separated, washed with water (2.0 V) and concentrated.The residual solvents and water were azeotropically removed with heptane(3.0 V×2) to give the crude product as yellow solid-oil mixture(dr=2.6:1). The crude was suspended in Heptane-MTBE (5:1, v/v, 3.0 V)and heated to 80° C. The resultant clear solution was cooled to roomtemperature (23° C.) over 3 hours (precipitation started at 45° C.). Thecrystals were collected by filtration, washed with: 1) heptane-MTBE (5:1v/v, 1.0 V); 2) heptane (1.0 V) and dried under N₂/vacuum to giveCompound AD as white powder (0.31 Wt, 0.31 eq, 0.08 eq). The motherliquor was concentrated to give Compound AS (0.69 Wt, dr=1:1).

Method 2: Compound AS (1 Wt, 1 V, dr=1:1) was dissolved in heptane-MTBE(5:1 v/v, 2.0 V) and KHMDS (0.50 M solution in toluene, 0.40 V, 0.07 eq)was added at 23° C. Stirring was continued for 10 minutes and themixture was cooled to 0° C. Compound AD (0.0001 Wt, 0.0001 eq) was addedand stirring was continued for an additional 30 minutes (precipitationincreased). 20 wt % NH₄Cl aq (0.20 Wt, 0.26 eq) was added under vigorousstirring. The resultant mixture was diluted with EtOAc (2.0 V) todissolve Compound AD precipitation. The organic layer was separated,washed with water (1.0 V) and concentrated. The residual solvents andwater were azeotropically removed with heptane (5 V×2) to give crudeproduct as yellow solid-oil mixture (dr=2.3:1). The crude was suspendedin heptane-MTBE (3:1 v/v, 1.5 V) and heated to 80° C. The resultantclear solution was cooled to 20° C. over 3 hours (precipitation startedat 50° C.). The crystals were collected by filtration, washed withheptane-MTBE (4:1 v/v, 1 V), and dried under N₂/vacuum to give CompoundAD as white powder (0.22 Wt, 0.22 eq, 0.04 eq).

Method 3 (CIDR): Compound AS (1 Wt, 1 V, dr=1:5) was dissolved inheptane (5 V) at 23° C. t-BuOK (1.0 M solution in THF, 0.29 V, 0.10 eq)was added and stirring was continued for 10 minutes. The precipitationswere collected by filtration, washed with heptane (10 V), and dried togive Compound AD as light tan powder (0.36 Wt, 0.36 eq, dr=7.3:1,filtrate dr=3.7:1).

Method 4: Compound AS (1 Wt, 1 V, 1 eq, dr=1:1.7) was dissolved intoluene (5.0 V) and cooled to −70˜−75° C. KHMDS (0.5 M solution intoluene, 0.500 eq, 2.88 V, 2.53 Wts) was added while maintaining aninternal temperature below −65° C. The resultant mixture was cooled to−70˜−75° C. again and stirring was continued at −70˜−75° C. for 4 hours.20 wt % NH₄Cl (aqueous solution, 2.00 Wts) was added while maintainingan internal temperature below −60° C. Upon complete addition, themixture was allowed to warm to 0° C. over a period of 1.5-2 hours. MTBE(4.00 V, 2.96 Wt) and water (4.00 V, 4.00 Wt) were added under stirringand the resultant biphasic mixture was allowed to partition. Organiclayer (dr=6.5:1) was separated, sequentially washed with: 1) 20 wt %citric acid (aqueous solution, 1.0 Wt); 2) water (3.00 V); 3) water(3.00 V) and partially concentrated to ˜2V under vacuum. The residue wassubjected to solvent exchange with heptane (6.00 V×2, partialconcentration to ˜2 V each time, under vacuum) and diluted withheptane-IPA (6:1 v/v, 3.5 V). The mixture was heated to 60° C., cooledto 15˜20° C. over 4 hours, and further stirred at 15˜20° C. overnight.Crystals were collected by filtration, rinsed with heptane-IPA (9:1 v/v,2.0 V) and dried under N₂/vacuum to give Compound AD (0.4 Wt, 0.4 eq,dr=57:1) as light tan powder.

¹H NMR (500 MHz, CDCl₃)

δ 4.40-4.44 (1H, m), 4.30 (1H, dd, J=6.5, 3.5 Hz), 4.09 (1H, dd, J=6.5,3.0 Hz), 3.72-3.77 (1H, m); 3.37 (1H, dd, J=10.0, 6.5 Hz), 2.91-2.99(1H, m), 2.35-2.39 (1H, m), 2.07-2.12 (1H, m), 1.97-2.03 (1H, m), 1.96(1H, dd, J=14.0, 4.0 Hz), 1.82 (1H, d, J=12.0 Hz), 1.58-1.70 (5H, m),1.50-1.58 (6H, m), 1.42-1.49 (1H, m), 1.32-1.40 (2H, m), 1.29 (3H, d,J=7.0 Hz), 1.11-1.20 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 122.95, 110.58, 78.29, 76.28, 75.92, 75.81, 72.16, 68.34, 43.80,40.51, 37.61, 34.52, 29.85, 28.92, 27.24, 25.33, 24.24, 23.84, 22.50,18.55

LRMS (ESI) m/z found 370.15 [M+Na]⁺

Melting Point 123° C.

Example 3: Synthesis of Compound AJ from Compound AD

Compound AD (1 Wt, 1 V) was suspended in AcOH (5.00 V, 31 eq) at 20° C.1.00 M HCl aq (2.48 V, 1.00 eq) was added and stirring was continued at20° C. for 5 hours. The reaction mixture was cooled to 0° C. and 50 wt %NaOH aq (2 Wt, 8 eq) was added while maintaining internal temperaturebelow 10° C. Heptane-MTBE (2:1 v/v, 10.0 V) was added and vigorousstirring was continued for 3 minutes. The organic layer was set asideand the aqueous layer was extracted with acetonitrile (10.0 V×2). All ofthe acetonitrile layers were combined, washed with brine (2.0 V) andconcentrated. The residual solvents were azeotropically removed withacetonitrile (8.0 V×2) to give the crude product as yellow solid (0.62Wt, 0.080 eq).

Crude Compound AJ (1 Wt, 1 V) was suspended in IPA (6.0 V) and heated to80° C. The resultant solution was cooled to room temperature over 1hour. The mixture was further cooled to 0° C. and stirring was continuedat 0° C. for an additional hour.

The precipitations were collected by filtration, washed with cold IPA(2.0 V), and dried to give Compound AJ as a white powder (0.72 Wt, 0.72eq).

¹H NMR (500 MHz, CDCl₃)

δ 4.37 (1H, dd, J=6.5, 5.0 Hz), 3.97-4.04 (1H, m), 3.88-3.89 (1H, m),3.74-3.79 (1H, m), 3.42 (1H, dd, J=10.0, 7.0 Hz), 2.91-2.99 (1H, m),2.56 (1H, br), 2.37-2.41 (1H, m), 2.27 (1H, br), 2.05-2.11 (1H, m),1.96-2.00 (1H, m), 1.82 (1H, d, J=11.5 Hz), 1.75 (1H, t, J=11.5 Hz),1.65-1.70 (1H, m), 1.54-1.61 (2H, m), 1.47-1.53 (1H, m), 1.32 (3H, d,7.0 Hz), 1.15-1.24 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 122.93, 77.71, 77.00 (overlapped with chloroform signal), 73.60,69.14, 68.45, 67.04, 43.66, 40.38, 29.88, 28.85, 28.37, 22.48, 18.53

¹³C NMR (125 MHz, acetone-d6)

δ 122.60, 77.77, 77.04, 73.32, 69.40, 68.34, 66.55, 44.02, 40.11, 29.93,28.74, 28.16, 22.25, 17.95

LRMS (ESI) m/z found 289.95 [M+Na]⁺

Melting Point 189° C.

Example 4: Synthesis of Compound AK from Compound AJ

Compound AJ (1 Wt, 1 V, 1 eq) was suspended in acetonitrile (5.00 V) andcooled to 0° C. 2-acetoxy-2-methylpropionyl bromide (0.938 Wt, 0.656 V)was added at a rate such that the internal temperature did not exceed 7°C. Upon complete addition, water (0.002 V, 3 mol %) was added andstirring was continued at 0° C. for an additional hour. The reactionmixture was diluted with MTBE (5.0 V). After internal temperaturedropped to 0° C., 10 wt % NaHCO₃ aq (5.0 V, 3.4 eq) was carefully addedunder vigorous stirring maintaining internal temperature below 7° C. andthe resultant mixture was allowed to partition. The organic layer wasset aside and the aqueous layer was extracted with MTBE (5.0 V). All ofthe organic layers were combined, sequentially washed with: 1) 10 wt %NaHCO₃ aq (2.0 V, 1.4 eq); 2) water (2.0 V); 3) brine (2.0 V), andconcentrated to give crude Compound AK as light brown oil (1.47 Wt, 1.04eq). The crude product was azeotropically dried with toluene (4 V×3) andused for next reaction without purification.

¹H NMR (500 MHz, CDCl₃)

δ 5.20 (1H, br), 4.38 (1H, dd, J=6.5, 3.5 Hz), 4.21-4.23 (1H, m), 4.04(1H, dd, J=10.0, 7.0 Hz), 3.79-3.83 (1H, m), 2.90-2.98 (1H, m),2.51-2.56 (2H, m), 2.30-2.34 (1H, m), 2.11-2.15 (1H, m), 2.07 (3H, s),1.65-1.71 (1H, m), 1.57-1.62 (3H, m), 1.49-1.55 (1H, m), 1.32 (3H, d,J=6.5 Hz), 1.21-1.30 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 169.39, 122.79, 78.13, 75.49, 75.42, 73.76, 68.45, 44.66, 43.48,40.11, 29.48, 28.88, 28.38, 22.40, 21.12, 18.46

LRMS (ESI) m/z found 393.96 [M+Na]⁺

Example 5: Synthesis of Compound AL from Compound AJ

Compound AJ (1 Wt, 1 V, 1 eq) was suspended in acetonitrile (3.0 V) andcooled to 0° C. 2-acetoxy-2-methylpropionyl bromide (1.02 Wt, 1.30 eq)was added at a rate such that the internal temperature did not exceed 2°C. Upon complete addition, an acetonitrile-water mixture (water (0.0020V, 0.030 eq) and acetonitrile (0.020 V)) were added and stirring wascontinued at 0° C. for 2 hours. Under vigorous stirring, 10 wt % NaHCO₃aq (5.0 V) was added at a rate such that the internal temperature didnot exceed 8° C. (CO₂ evolution). Toluene (4.3 Wt, 5.0 V) was added andvigorous stirring was continued for 3 minutes. The mixture was allowedto partition and the organic layer was set aside. The aqueous layer wasextracted with toluene (2.6 Wt, 3.0 V). All of the organic layers werecombined and sequentially washed with: 1) 10 wt % NaHCO₃ aq (3.0 V); 2)water (2.0 V).

The organic layer was transferred to a reactor and subjected todistillation under atmospheric pressure to remove 5 Wt of solvent. Thedistillation included heating the organic layer to 90° C. to remove theacetonitrile and then heating the mixture to about 110° C. to remove thetoluene. After cooling to 80° C., toluene (2.50 Wt, 3 V) was addedfollowed by DBU (1.12 V, 1.14 Wt, 2.00 eq). The mixture was re-heated to100° C. and vigorously stirred for 17 hours. The reaction mixture wascooled to 0° C. and 1.00 M HCl aq (4.5 V, 1.2 eq) was added at a ratesuch that the internal temperature did not exceed 8° C. The resultantmixture was allowed to partition. The organic layer was set aside andaqueous layer was extracted with toluene (1.73 Wt, 2.0 V). All of theorganic layers were combined, sequentially washed with: 1) 1.00 M HC1 aq(0.50 V, 0.13 eq); 2) 10 wt % NaHCO₃ aq (1.0 V); 3) water (2.0 Wt, 2.0V), and concentrated. The residual toluene was azeotropically removedwith IPA (2.0 V) to give the crude product as yellow solid. CrudeCompound AL was suspended in IPA (5.0 V) and heated to 80° C. Theresultant solution was cooled to 0° C. over 2 hours and stirring wascontinued at 0° C. for an additional 30 minutes. Crystals were collectedby filtration, washed with cold IPA (1 V) followed by heptane (1 V), anddried to give Compound AL as white powder (0.64 Wt, 0.59 eq). The motherliquor was concentrated and diluted with IPA-heptane (1:1 v/v, 1.0 V). Awhite precipitation was formed, collected by filtration, washed with: 1)IPA-heptane (1:1 v/v, 0.4 V); 2) heptane (0.4 V), and dried to giveadditional Compound AL (0.043 Wt, 0.040 eq).

Example 6: Synthesis of Compound AL from Compound AK

Compound AK (1 Wt, 1 V, 1 eq) was dissolved in toluene (5.0 V). DBU(0.818 Wt, 0.803 V, 2.0 eq) was added at 23° C. and the mixture washeated to 100° C. Upon complete consumption of Compound AK, the reactionmixture was cooled to 10° C. and 1M HC1 (3.5 V, 1.3 eq) was added. Theresultant mixture was vigorously stirred for 5 minutes and allowed topartition. The organic layer was set aside and the aqueous layer wasextracted with MTBE (5.0 V). All organic layers were combined,sequentially washed with: 1) water (2.0 V); 2) 10 wt % NaHCO₃ solution(2.0 V); 3) water (2.0 V), and concentrated to give a mixture of lightbrown oil and water. The residual water was azeotropically removed withheptane (3.0 V×3) to give crude Compound AL as yellow solid (0.65 Wt,0.83 eq)

¹H NMR (500 MHz, CDCl₃)

δ 6.16 (1H, d, J=10 Hz), 5.60-5.63 (1H, m), 5.01-5.02 (1H, m), 4.34-4.36(1H, m), 3.80-3.85 (1H, m), 3.42 (1H, dd, J=5.0, 2.0 Hz), 2.93-3.01 (1H,m), 2.53-2.57 (1H, m), 2.07-2.12 (1H, m) 2.03 (3H, s), 1.56-1.72 (4H,m), 1.49-1.55 (1H, m), 1.32 (3H, d, J=6.5 Hz), 1.22-1.30 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 170.10, 142.16, 122.82, 122.42, 79.43, 75.26, 74.81, 69.52, 68.48,40.36, 29.62, 28.90, 28.77, 22.49, 21.26, 18.54

LRMS (ESI) m/z found 314.04 [M+Na]⁺

Melting Point 92° C.

Example 7: Synthesis of Compound AM from Compound AL

Compound AL (1 Wt, 1 V, 1 eq) was dissolved in MeOH-DCM (5:3 v/v, 8.0 V)and cooled to −47° C. 03 was bubbled into the mixture maintaining aninternal temperature below −42° C. Upon complete consumption of CompoundAL, excess O₃ was purged by N₂ bubbling until the peroxide test for thereactor outlet was negative.

The reaction mixture was then allowed to warm to −25° C. and NaBH₄(0.0753 Wt, 0.580 eq) was added while maintaining an internaltemperature below −17° C. Upon complete addition, the mixture wasstirred at −20° C. for 1 hour and then allowed to warm to 0° C. NaBH₄(granules, 0.0753 Wt, 0.580 eq) was added (while maintaining an internaltemperature below 3° C.) and stirring was continued at 0° C. for onehour.

K₂CO₃ (0.712 Wt, 1.50 eq) was added at 0° C. and the reaction wasallowed to warm to 20° C. Upon complete consumption of the acetateintermediate (approx 4 hours), the reaction mixture was cooled to 0° C.and 10 wt % HCl aq (5.1 Wt, 4.1 eq) was added under vigorous stirring toadjust the pH to 6-7.

The resultant biphasic mixture was partially concentrated (to approx 5.6Wt) for removal volatiles, re-diluted with water-THF (1:1 v/v, 4.0 V),and cooled to 15° C. NaIO₄ (1.47 Wt, 2.00 eq) was added and theresultant slurry was stirred at 20° C. until complete consumption oftriol (approx. 3 hours). The reaction mixture was then diluted withEtOAc (6.0 V), stirred vigorously for 5 minutes, and filtered through apad of Celite (2 Wt). The filtrate (F-1) was separated and set aside andthe filter cake was washed with EtOAc-EtOH (9:1 v/v, 4.0 V) (filtrate:F-2). NaCl (1.0 Wt) was added to F-1 and the resultant mixture wasstirred vigorously for 5 minutes and allowed to partition. The organiclayer was set aside and the aqueous layer was extracted with F-2. All ofthe organic layers were combined, sequentially washed with: 1) 10 wt %Na₂S₂O₃ aq (1.0 Wt); 2) water (1.0 V); 3) water (1.0 V) and concentratedto give a white solid. The residual water and solvents wereazeotropically removed with EtOAc (6.0 V×3) to give the crude product aswhite solid (0.84 Wt, 0.96 eq). The crude was suspended in heptane-EtOAc(1:1 v/v, 3.5 V) and heated to 80° C. The resultant solution was cooledto room temperature over 2 hours (the precipitation started at ˜65° C.).The mixture was further cooled to 0° C. and stirring was continued foran additional hour. The crystals were collected by filtration, washedwith cold heptane-EtOAc (1:1 v/v, 1.8 V), and dried under N₂/vacuum togive Compound AM as white powder (0.58 Wt, 0.67 eq). The mother liquorwas concentrated, suspended in heptane-EtOAc (4:3 v/v, 0.9 V), andheated to 80° C. The resultant clear solution was cooled to 20° C. over2 hours. The mixture was further cooled to 0° C. and stirring wascontinued for an additional hour. The crystals were collected byfiltration, washed with cold heptane-EtOAc (4:3 v/v, 0.50 V) and driedunder N₂/vacuum to give additional Compound AM as white powder (0.068Wt, 0.08 eq).

¹H NMR (for major anomer, 500 MHz, CDCl₃)

δ 4.96 (1H, s), 4.17 (1H, dd, J=6.0, 3.5 Hz), 3.90 (1 h, d, J=9.5 Hz),3.82-3.74 (2H, m), 3.41 (1H, dd, J=10, 3.0 Hz), 3.01 (1H, s), 2.95-2.85(1H, m), 2.51-2.45 (1H, m), 2.22-2.15 (1H, m), 1.72-1.64 (1H, m),1.63-1.48 (3H, m), 1.29 (3H, d, J=13 Hz), 1.30-1.18 (1H, m)

¹³C NMR (for major anomer, 125 MHz, CDCl₃)

δ 122.81, 92.46, 77.17, 75.70, 72.43, 71.18, 68.36, 40.28, 29.82, 28.70,28.40, 22.42, 18.52

LRMS (ESI) m/z found 307.99 [M+MeOH+Na]⁺

Melting Point 116° C.

Example 8: Synthesis of Compound AN from Compound AM

Compound AM (1 Wt, 1 V, 1 eq) was suspended in acetonitrile (4.0 V) andcooled to 10° C. LiCl (0.184 Wt, 1.10 eq) was added followed byN,N-diisopropylethylamine (0.825 V, 1.20 eq). After the internaltemperature dropped to 10° C., trimethyl phosphonoacetate (0.703 V, 1.10eq) was added at a rate such that the internal temperature did notexceed 13° C. Upon complete addition, the reaction was stirred at 10° C.for one hour and was then allowed to warm to 20° C. Stirring wascontinued at 20° C. until complete consumption of Compound AM. Thereaction mixture was diluted with MTBE (8.0 V) and cooled to 0° C. 1.00M HCl aq (5.0V, 1.5 eq) was added under vigorous stirring whilemaintaining the internal temperature below 8° C. and the resultantbiphasic mixture was allowed to partition. The organic layer was setaside and the aqueous layer was extracted with MTBE (4.0 V & 2.0 V). Allof the organic layers were combined, sequentially washed with: 1) 10 wt% NaHCO₃ aq (3.0 V); 2) water (2.0 V) and concentrated to give CompoundAN as pale yellow oil (E:Z ˜20:1).

¹H NMR (500 MHz, CDCl₃)

δ 6.87 (1H, dd, J=16.0, 3.5 Hz), 6.02 (1H, dd, J=16.0, 1.5 Hz),4.81-4.86 (1H, m), 4.02 (1H, dd, J=9.0, 6.0 Hz), 3.86-3.91 (1H, m), 3.73(3H, s), 3.46-3.52 (2H, m), 2.87-2.94 (1H, m), 2.51 (1H, dd, J=14.0,10.0 Hz), 2.14 (1H, dd, J=7.5, 5.5 Hz), 1.92-1.98 (1H, m), 1.75-1.83(1H, m), 1.66-1.74 (3H, m), 1.61-1.45 (1H, m), 1.33 (3H, d, J=7.0 Hz),1.27-1.35 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 166.95, 148.24, 123.08, 120.00, 84.03, 74.31, 74.25, 67.85, 67.77,51.85, 40.23, 35.52, 26.80, 24.18, 22.27, 18.30

LRMS (ESI) m/z found 332.05 [M+Na]⁺

Example 9: Synthesis of Compound AO from Compound AN

A reactor was charged with PtO₂ (0.73 wt %, 1.0 mol %) under an N₂atmosphere. A solution of Compound AN in MeOH (10.0 V) was added underN₂. The resultant slurry was cooled to 15° C. and stirred under anatmosphere of 1.04 bar H₂. After two hours, the reaction was warmed to20° C. and stirring was continued until complete consumption of CompoundAN. The reaction mixture was filtered through a pad of celite (1 Wt) andthe filter cake was washed with MeOH (5.0 V). The filtrate wasconcentrated and residual MeOH was azeotropically removed with anhydrousDCM (3.0 V×2) to give Compound AO as gray-colored oil (1.06 Wt, 1.05eq). The crude product was used for next reaction without purification.

¹H NMR (500 MHz, CDCl₃)

δ 4.18-4.23 (1H, m), 3.82-3.91 (2H, m), 3.67 (3H, s), 3.53 (2H, d, J=6.5Hz), 2.86-2.93 (1H, m), 2.40-2.46 (1H, m), 2.31-2.38 (2H, m), 2.17 (1H,t, J=7.0 Hz), 1.85-1.92 (1H, m), 1.59-1.84 (6H, m), 1.49 (1H, dd,J=14.0, 5.5 Hz), 1.32 (3H, d, J=7.5 Hz), 1.23-1.30 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 173.90, 123.10, 84.23, 74.90, 73.28, 68.31, 67.73, 51.81, 40.28,35.99, 31.75, 30.78, 27.12, 24.03, 22.27, 18.32

LRMS (ESI) m/z found 334.08 [M+Na]⁺

Example 10: Synthesis of Compound AF from Compound AO

Compound AO (1 Wt, 1 V, 1 eq) was dissolved in DCM (4.50 V). TEA (1.16V, 0.84 Wt, 2.60 eq) was added and the mixture was cooled to −70° C. Asolution of Tf₂O (0.702 V, 1.30 eq) in DCM (1.50 V) was added at a ratesuch that the internal temperature did not exceed −65° C. Upon completeaddition, the reaction was stirred at −73° C. for 1.5 hours, allowed towarm to −20° C., and stirred at −20° C. for an additional 30 minutes.

DMF (3.0 V) was added and the mixture was allowed to warm to 0° C. NaI(0.674 Wt, 1.40 eq) was added and the reaction was further warmed to 23°C. Upon complete consumption of the triflate (Compound AT), the reactionmixture was diluted with heptane (8.0 V) and cooled to 0° C. Water (9.0V) was added while maintaining an internal temperature below 10° C. Theresultant biphasic mixture was stirred vigorously for 3 minutes and thenallowed to partition. The organic layer was set aside and the aqueouslayer was extracted with MTBE (6.0 V). All of the organic layers werecombined, sequentially washed with: 1) 1.00 M HCl aq (5.00 V, 1.56 eq);2) 10 wt % NaHCO₃ aq (2.0 V); 3) 10 wt % Na₂S₂O₃ aq (2.0 V), 4) water(2.0 V); 5) water (2.0 V) and concentrated. The residue was dissolved inMTBE (6.0 V) and silica gel (1.0 Wt) was added. The resultant slurry wasstirred at 22° C. for 5 minutes and then filtered. The silica gel on thefilter was washed with MTBE (8.0 V) and the filtrate was concentrated togive crude product as reddish solid (1.35 Wt, 1.00 eq).

Compound AF (1.35 Wt, 1.00 eq) was suspended in MTBE (1.4 V) and heatedto 45° C. Heptane (2.8 V) was added while maintaining an internaltemperature between 40° C. and 45° C. The resultant clear solution wascooled to 22° C. over 1 hour and then stirred at 22° C. for 2 hours. Themixture was cooled to 0° C. and stirring was continued for an additional2 hours. The precipitations were collected by filtration, washed withpre-cooled (0° C.) heptane-MTBE (1:3 v/v, 2.8 V) and dried underN₂/vacuum for one hour to give Compound AF as light tan powder (0.98 Wt,0.72 eq). The mother liquor was concentrated and re-dissolved in MTBE(0.33 V). Heptane (0.33 V) was added and the resultant clear solutionwas cooled to 0° C. A very small amount of Compound AF crystal (from the1^(st) crop) was added for seeding and stirring was continued at 0° C.for 15 hours. The precipitations were collected by filtration, washedwith pre-cooled (0° C.) heptane-MTBE (1:2 v/v, 0.33 V), and dried underN₂/vacuum for 1 hour to give additional Compound AF as light tan powder(0.046 Wt, 0.034 eq).

Compound AT

¹H NMR (500 MHz, CDCl₃)

δ 4.46 (1H, d, J=10.5 Hz), 4.38 (1H, d, J=10.5 Hz), 4.21-4.26 (1H, m),3.89 (1H, dd, J=8.5, 6.0 Hz), 3.81-3.86 (1H, m), 3.68 (3H, s), 2.93-3.00(1H, m), 2.41-2.50 (2H, m), 2.33-2.39 (1H, m), 1.91-1.97 (1H, m),1.64-1.92 (6H, m), 1.45 (1H, dd, J=14.5, 5.5 Hz), 1.25-1.35 (1H, m),1.32 (3H, d, J=7.0 Hz)

¹³C NMR (125 MHz, CDCl₃)

δ 173.62, 122.86, 117.51, 81.84, 78.54, 74.57, 73.08, 68.63, 51.94,40.16, 35.28, 31.77, 30.64, 27.13, 23.95, 22.33, 18.42

LRMS (ESI) m/z found 446.12 [M+Na]⁺

Compound AF

¹H NMR (500 MHz, CDCl₃)

δ 4.21-4.26 (1H, m), 3.78-3.83 (2H, m), 3.67 (3H, s), 3.44 (1H, d,J=10.0 Hz), 3.37 (1H, d, J=10.0 Hz), 2.99-3.03 (1H, m), 2.49 (1H, dd,J=9.0, 8.5 Hz), 2.42-2.47 (1H, m), 2.32-2.38 (1H, m), 1.80-1.89 (3H, m),1.63-1.75 (5H, m), 1.33 (3H, d, J=7.5 Hz), 1.24-1.30 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 173.74, 122.89, 81.75, 76.07, 75.10, 68.24, 51.86, 40.52, 39.00,31.78, 30.75, 27.09, 24.36, 22.53, 18.72, 18.51

LRMS (ESI) m/z found 444.02 [M+Na]⁺

Melting Point 69.5° C.

Example 11: Synthesis of Compound AP from Compound AF

Compound AF (1 Wt, 1 V, 1 eq) was dissolved in toluene (5.0 V) andcooled to 10° C. LiBH₄ (2.0 M solution in THF, 2.4 V, 2.0 eq) was addedand stirring was continued at 20° C. for 18 hours. The reaction mixturewas cooled to 0° C. and slowly poured into a pre-cooled (0° C.) mixtureof EtOAc (6 V) and 1.0 M HCl aq (6.0 V, 2.5 eq) under vigorous stirring.The reactor was rinsed with EtOAc (2 V) and the resultant wash wascombined with the biphasic mixture. The organic layer was set aside andthe aqueous layer was extracted with EtOAc (5.0 V). All of the organiclayers were combined, sequentially washed with: 1) 10 wt % NaHCO₃ aq (2V); 2) water (2 V) and concentrated. The residual water wasazeotropically removed with toluene (5 V×2) to give Compound AP (0.93Wt, 0.89 eq).

¹H NMR (500 MHz, CDCl₃)

δ 4.24-4.30 (1H, m), 3.86 (1H, dd, J=8.5, 6.0 Hz), 3.78-3.83 (1H, m),3.62-3.68 (2H, m), 3.44 (1H, d, J=10.5 Hz), 3.38 (1H, d, J=10.5 Hz),2.99-3.04 (1H, m), 2.51 (1H, dd, J=14.0, 8.5 Hz), 2.06 (1H, t, J=6.0Hz), 1.86-1.92 (1H, m), 1.59-1.78 (9H, m), 1.33 (3H, d, J=7.0 Hz),1.24-1.31 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 122.94, 82.70, 76.27, 76.25, 68.42, 62.77, 40.50, 39.08, 33.72, 29.67,27.25, 24.59, 22.55, 19.08, 18.51

LRMS (ESI) m/z found 416.02 [M+Na]⁺

Example 12: Synthesis of Compound AU from Compound AP

An inert reactor was charged with Zn powder (2.5 Wt, 15 eq) at 23° C.MeOH (5.0 V) was added followed by AcOH (2.0 V, 14 eq). The resultantslurry was stirred at 23° C. for 20 minutes and then cooled to 0° C. Asolution of Compound AP (1 Wt, 1 V, 1 eq) in MeOH (5.0 V) was added andvigorous stirring was continued at 0° C. for 3 hours and at 23° C. for1.5 hours. The reaction mixture was diluted with EtOAc (20 V). Excess Znpowder was removed by filtration and rinsed with EtOAc (10 V). Thefiltrate was washed with 1.00 M HCl aq (10 V). The organic layer was setaside and the aqueous layer was extracted with EtOAc (20 V). All of theorganic layers were combined, sequentially washed with: 1) 10 wt %NaHCO₃ aq (20 V); 2) 10 wt % Na₂S₂O₃ aq (8 V); 3) brine (8 V), andconcentrated to give the crude product as pale yellow oil. The crude waspurified by flash column chromatography (Biotage, heptane-EtOAc3:7→2:8→0:10) to give Compound AU (0.62 Wt, 0.90 eq) as pale yellow oil.

¹H NMR (500 MHz, CDCl₃)

δ 5.01 (1H, s), 4.85 (1H, s), 4.41 (1H, br), 4.08-4.12 (1H, m), 3.93(1H, br), 3.60-3.68 (2H, m), 3.12 (1H, br), 2.97-3.05 (1H, m), 2.69-2.73(1H, m), 2.45 (1H, br), 2.29-2.33 (1H, m), 1.53-1.80 (10H, m), 1.33 (3H,d, J=7.5 Hz)

¹³C NMR (125 MHz, CDCl₃)

δ 150.95, 123.29, 105.49, 79.66, 77.69, 68.79, 62.84, 41.83, 39.03,34.33, 32.11, 30.89, 29.80, 22.93, 18.61

LRMS (ESI) m/z found 289.96 [M+Na]⁺

Example 13: Synthesis of Compound AR from Compound AU

Compound AU (1 Wt, 1 V, 1 eq) was dissolved in MeOH (2.0 V). The mixturewas cooled to 0° C. and HCl (6 M solution in IPA, 2.0 V, 13 eq) wasadded. The reaction was allowed to warm to 23° C. and stirring wascontinued until complete consumption of Compound AU (approx. 20 hours).The reaction mixture was diluted with toluene (8.0 V) and water (4.0 V)and the resultant biphasic mixture was heated at 60° C. for 3 hours.After cooling down, organic layer was set aside and aqueous layer wasextracted with EtOAc (8.0 V). All organic layers were combined,sequentially washed with: 1) 10 wt % NaHCO₃ aq (2.0 V); 2) brine (2.0V); 3) water (2.0 V), and concentrated to give crude Compound AR (0.93Wt, 0.93 eq) as pale yellow oil. The crude product was azeotropicallydried with toluene (8 V×2) and used for next reaction withoutpurification.

¹H NMR (500 MHz, CDCl₃)

δ 4.98-4.99 (1H, m), 4.84-4.85 (1H, m), 4.49-4.54 (1H, m), 4.39 (1H, d,J=10.5 Hz), 4.00-4.05 (1H, m), 3.59-3.68 (2H, m), 2.63-2.72 (2H, m),2.56-2.62 (1H, m), 2.25-2.30 (1H, m), 2.08-2.14 (1H, m), 1.97-2.02 (1H,m), 1.52-1.82 (7H, m), 1.26 (3H, d, J=7.5 Hz), 1.24-1.34 (1H, m)

¹³C NMR (125 MHz, CDCl₃)

δ 180.34, 151.14, 105.39, 79.71, 78.84, 77.54, 62.72, 39.02, 35.69,34.15, 32.19, 32.16, 31.50, 29.64, 16.02

LRMS (ESI) m/z found 290.99 [M+Na]⁺

Example 14: Synthesis of Compound AH from Compound AR

Compound AR (1 Wt, 1 V, 1 eq) was dissolved in DMF (2.0 vols) andimidazole (0.330 Wt, 1.30 eq) was added at 23° C. (endothermic). Uponcomplete dissolution of imidazole, the mixture was cooled to 10° C. andtert-butylchlorodiphenylsilane (TBDPSCl, 0.969 V, 1.02 Wt, 1.00 eq) wasadded. The reaction mixture was stirred at 10° C. for 1 hour, allowed towarm to 23° C., and stirred until complete consumption of Compound AR(approx. 3 hours). The reaction mixture was diluted with Heptane-MTBE1:1 (8.0 V) and cooled to 10° C. Water (8.0 V) was added under vigorousstirring and the resultant mixture was allowed to partition. The aqueouslayer was set aside. The organic layer was further washed with water(1.0 V) and concentrated. Residual water and solvents wereazeotropically removed with toluene (8.0 V×2) to give Compound AH ascolorless oil (1.98 Wt, 100%). The crude product was used for nextreaction without purification

¹H NMR (500 MHz, CDCl₃)

δ 7.65-7.67 (4H, m), 7.36-7.44 (6H, m), 4.99 (1H, dd, J=4.0, 2.5 Hz),4.84 (1H, dd, J=4.0, 2.5 Hz), 4.50-4.55 (1H, m), 4.35 (1H, d, J=9.0 Hz),3.97-4.02 (1H, m), 3.66-3.70 (2H, m), 2.66-2.71 (1H, m), 2.61-2.66 (1H,m), 2.22-2.27 (1H, m), 2.08-2.14 (1H, m), 1.97-2.03 (1H, m), 1.50-1.81(8H, m), 1.28 (3H, d, J=7.5 Hz), 1.04 (9H, s)

¹³C NMR (125 MHz, CDCl₃)

δ 180.18, 151.68, 135.79 (4C), 134.21 (2C), 129.84 (2C), 127.89 (4C),105.27, 79.58, 78.83, 77.38, 64.02, 39.08, 35.78, 34.20, 32.29, 31.76,31.60, 29.31, 27.16 (3C), 19.48, 16.15

LRMS (ESI) m/z found 529.26 [M+Na]⁺

Example 15: Synthesis of Compound AV from Compound AH

An inert reactor was charged with N,O-Dimethylhydroxylaminehydrochloride (0.298 Wt, 1.55 eq). DCM (2.0 V) was added and theresultant slurry was cooled to −5° C. Trimethylaluminum (2.0 M solutionin toluene, 1.48 V, 1.50 eq) was slowly added at a rate such that theinternal temperature did not exceed 3° C. Upon complete addition, themixture was stirred at 0° C. for 30 minutes. A solution of Compound AH(1 Wt, 1 V, 1 eq) in DCM (3.0 V) was added at a rate such that theinternal temperature did not exceed 5° C. and stirring was continued at0° C. until complete consumption of Compound AH. Another reactor wascharged with 20 wt % Rochelle salt (10 Wt) and MTBE (10 V), and cooledto 0° C. The reaction mixture was transferred into the pre-cooledbiphasic mixture while maintaining the internal temperature below 5° C.The resultant mixture was vigorously stirred at 0° C. for 30 minutes andthen allowed to partition. The organic layer was set aside and theaqueous layer was extracted with MTBE (10 V). All of the organic layerswere combined, sequentially washed with: 1) 20 wt % Rochelle saltsolution (5 Wt); 2) water (3 V); 3) brine (2 V), and concentrated togive the crude product as pale yellow oil. The crude product wasazeotropically dried with toluene (5 V×2) and used for the followingreaction without purification.

The crude hydroxyamide was dissolved in DMF (2.0 V) and cooled to 10° C.Imidazole (0.161 Wt, 1.20 eq) was added followed by TBSCl (0.297 Wt,1.00 eq). The reaction was stirred at 15° C. for 2 hours, allowed towarm to 23° C., and stirred until complete consumption of thehydroxyamide intermediate. The reaction mixture was diluted withheptane-MTBE 1:1 (10 V) and cooled to 0° C. Water (8 V) was added andthe resultant biphasic mixture was vigorously stirred and allowed topartition. The organic layer was set aside and aqueous layer wasextracted with heptane-MTBE (1:1 v/v, 8.0 V). All of the organic layerswere combined, sequentially washed with: 1) water (3.0 V); 2) brine (3.0V), and concentrated to give crude Compound AV (1.35 Wt, 0.99 eq) as apale yellow oil.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by thefollowing claims. The contents of all references, patents, and patentapplications cited throughout this application are hereby incorporatedby reference. The appropriate components, processes, and methods ofthose patents, applications and other documents may be selected for thepresent invention and embodiments thereof.

The invention claimed is:
 1. A method of obtaining a substantiallydiastereomerically pure composition of a compound of formula (I),comprising: crystallizing said compound of formula (I) from a mixture ofdiastereomers under appropriate crystallization conditions, wherein saidcompound of formula (I) is:

wherein: z is a single or double bond, provided that when z is a doublebond, X² is C and Y¹ is hydrogen; and provided that when z is a singlebond, X² is CH or O; X¹ is O, S, or CN, provided that when X¹ is CN orS, X² is O; Y¹ is a halide, hydrogen or O-L², or absent when X² is O; L¹and L² are independently selected from hydrogen and a protecting groupselected from the group consisting of C₁-C₁₂ alkylcarbonyl, C₁-C₆ ester,C₁-C₆ alkyl, C₁-C₁₅ alkyl silyl, aryl (C₁-C₆) alkyl, carbonate, andC₁-C₆ alkoxy-(C₁-C₆) alkyl groups, or L¹ and L² together are aprotecting group selected from the group consisting of pyran, cyclicC₁-C₆ acetal, cyclic C₃-C₇ ketal, and cyclic carbonate, provided thatwhen X¹ is CN, L¹ is absent; or a salt thereof.
 2. The method of claim1, wherein which the ratio of said compound of formula (I) to thecompound with the opposite stereochemistry at the chiral centerindicated with an asterisk is at least 20:1.
 3. The method of claim 1,wherein at least one of L¹ and L² is a protecting group selected fromthe group consisting of methoxymethyl, trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, methyl,t-butyl, 3,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, and trityl, or L¹and L² together are cycloheptylidine.
 4. The method of claim 1, whereinat least one of L¹ and L² is C₁ alkyl carbonyl, or L¹ and L² togetherare acetonide, benzylidene, pyran, cyclohexylidene, or cyclopentylidene.5. The method of claim 1, wherein said compound of formula (I) is offormula (Ib):

wherein L^(1a) and L^(1b) are independently selected from hydrogen and aprotecting group selected from the group consisting of C₁-C₆ alkyl, aryl(C₁-C₆) alkyl, silyl (C₁-C₁₀), and C₁-C₆ alkyl ester, or L^(1a) andL^(1b) together are a divalent protecting group, selected from the groupconsisting of cyclic C₁-C₆ acetal, cyclic C₃-C₇ ketal, and cycliccarbonate.
 6. A method of making a substantially diastereomerically purecomposition of a compound of formula (Ib) from a compound of formula(Ia), wherein the compound of formula (Ia) is:

and the compound of formula (Ib) is:

wherein L^(1a) and L^(1b) are independently selected from hydrogen and aprotecting group selected from the group consisting of C₁-C₆ alkyl, aryl(C₁-C₆) alkyl, silyl (C₁-C₁₀), and C₁-C₆ alkyl ester, or L^(1a) andL^(1b) together are a divalent protecting group selected from the groupconsisting of cyclic C₁-C₆ acetal, cyclic C₃-C₇ ketal, and cycliccarbonate, provided that L^(1a) of formulae (Ia) and (Ib) are the sameand L^(1b) of formulae (Ia) and (Ib) are the same, said methodcomprising: reacting the compound of formula (Ia) under alkylatingconditions to form a mixture comprising the compound of formula (Ib) anddiastereomers thereof; and crystallizing the compound of formula (Ib)from the mixture, under appropriate crystallization conditions.
 7. Themethod of claim 6, wherein the ratio of said compound of formula (Ib) tothe compound with the opposite stereochemistry at the chiral centerindicated with an asterisk is at least 20:1.
 8. The method of claim 6,wherein the divalent protecting group is a cyclohexylidine protectinggroup.